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1.
Blood ; 144(3): 308-322, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-38657197

RESUMO

ABSTRACT: Thrombotic microangiopathy (TMA) is characterized by immunothrombosis and life-threatening organ failure but the precise underlying mechanism driving its pathogenesis remains elusive. In this study, we hypothesized that gasdermin D (GSDMD), a pore-forming protein that serves as the final downstream effector of the pyroptosis/interleukin-1ß (IL-1ß) pathway, contributes to TMA and its consequences by amplifying neutrophil maturation and subsequent necrosis. Using a murine model of focal crystalline TMA, we found that Gsdmd deficiency ameliorated immunothrombosis, acute tissue injury, and failure. Gsdmd-/- mice exhibited a decrease in mature IL-1ß, as well as in neutrophil maturation, ß2-integrin activation, and recruitment to TMA lesions, in which they formed reduced neutrophil extracellular traps in both arteries and interstitial tissue. The GSDMD inhibitor disulfiram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD-deficient, human-induced, pluripotent stem cell-derived neutrophils confirmed the involvement of GSDMD in neutrophil ß2-integrin activation, maturation, and pyroptosis. Both prophylactic and therapeutic administration of disulfiram protected the mice from focal TMA, acute tissue injury, and failure. Our data identified GSDMD as a key mediator of focal crystalline TMA and its consequences, including ischemic tissue infarction and organ failure. GSDMD could potentially serve as a therapeutic target for the systemic forms of TMA.


Assuntos
Gasderminas , Neutrófilos , Proteínas de Ligação a Fosfato , Microangiopatias Trombóticas , Animais , Humanos , Camundongos , Antígenos CD18/metabolismo , Antígenos CD18/genética , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/imunologia , Inflamação/patologia , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Piroptose , Microangiopatias Trombóticas/patologia , Microangiopatias Trombóticas/metabolismo , Microangiopatias Trombóticas/imunologia , Microangiopatias Trombóticas/etiologia
2.
Chem Rev ; 123(19): 11269-11335, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37751573

RESUMO

Late-stage functionalization (LSF) constitutes a powerful strategy for the assembly or diversification of novel molecular entities with improved physicochemical or biological activities. LSF can thus greatly accelerate the development of medicinally relevant compounds, crop protecting agents, and functional materials. Electrochemical molecular synthesis has emerged as an environmentally friendly platform for the transformation of organic compounds. Over the past decade, electrochemical late-stage functionalization (eLSF) has gained major momentum, which is summarized herein up to February 2023.

3.
Kidney Int ; 106(5): 819-825, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39142565

RESUMO

Cholesterol crystal embolism (CCE) implies immunothrombosis, tissue necrosis, and organ failure but no specific treatments are available. As CCE involves complement activation, we speculated that inhibitors of the C5a/C5aR axis would be sufficient to attenuate the consequences of CCE like that with systemic vasculitis. Cholesterol microcrystal injection into the kidney artery of wild-type mice initiated intra-kidney immunothrombosis within a few hours followed by a sudden drop of glomerular filtration rate and ischemic kidney necrosis after 24 hours. Genetic deficiency of either C3 or C5aR prevented immunothrombosis, glomerular filtration rate drop, and ischemic necrosis at 24 hours as did preemptive treatment with inhibitors of either C5a or C5aR. Delayed C5a blockade after crystal injection still resolved crystal clots and prevented all consequences. Thus, selective blockade of C5a or C5aR is sufficient to attenuate the consequences of established CCE and prospective inhibition in high-risk patients may be clinically feasible and safe.


Assuntos
Complemento C3 , Complemento C5a , Modelos Animais de Doenças , Embolia de Colesterol , Receptor da Anafilatoxina C5a , Animais , Masculino , Camundongos , Complemento C3/metabolismo , Complemento C3/antagonistas & inibidores , Complemento C3/imunologia , Complemento C5a/antagonistas & inibidores , Complemento C5a/imunologia , Complemento C5a/metabolismo , Embolia de Colesterol/complicações , Embolia de Colesterol/diagnóstico , Rim/patologia , Rim/imunologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/imunologia , Microvasos/efeitos dos fármacos , Microvasos/patologia , Necrose , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Trombose/etiologia , Trombose/imunologia , Trombose/prevenção & controle
4.
Anal Chem ; 96(6): 2534-2542, 2024 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-38302490

RESUMO

Cerebrospinal fluid (CSF) biomarkers are more sensitive than the Movement Disorder Society (MDS) criteria for detecting prodromal Parkinson's disease (PD). Early detection of PD provides the best chance for successful implementation of disease-modifying treatments, making it crucial to effectively identify CSF extracted from PD patients or normal individuals. In this study, an intelligent sensor array was built by using three metal-organic frameworks (MOFs) that exhibited varying catalytic kinetics after reacting with potential protein markers. Machine learning algorithms were used to process fingerprint response patterns, allowing for qualitative and quantitative assessment of the proteins. The results were robust and capable of discriminating between PD and non-PD patients via CSF detection. The k-nearest neighbor regression algorithm was used to predict MDS scores with a minimum mean square error of 38.88. The intelligent MOF sensor array is expected to promote the detection of CSF biomarkers due to its ability to identify multiple targets and could be used in conjunction with MDS criteria and other techniques to diagnose PD more sensitively and selectively.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Diagnóstico Precoce , Algoritmos , Aprendizado de Máquina
5.
Opt Lett ; 49(2): 254-257, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38194541

RESUMO

We demonstrate the InGaN/GaN-based monolithic micro-pyramid white (MPW) vertical LED (VLED) grown on (-201)-oriented ß-Ga2O3 substrate by selective area growth. The transmission electron microscopy (TEM) reveals an almost defect-free GaN pyramid structure on (10-11) sidewalls, including stacked dual-wavelength multi-quantum wells (MQWs). From the electroluminescence (EL) spectra of the fabricated MPW VLED, a white light emission with a high color rendering index (CRI) of 97.4 is achieved. Furthermore, the simulation shows that the light extraction efficiency (LEE) of the MPW VLED is at least 4 times higher compared with the conventional planar LED. These results show that the MPW VLED grown on ß-Ga2O3 has great potential for highly efficient phosphor-free white light emission.

6.
Cancer Cell Int ; 24(1): 119, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38553712

RESUMO

OBJECTIVE: This study aimed to construct a model based on 23 enrolled molecules to evaluate prognoses of pT2/3N0M0 esophageal squamous cell carcinoma (ESCC) patients with up to 20 years of follow-up. METHODS: The lasso-Cox model was used to identify the candidate molecule. A nomogram was conducted to develop the survival model (molecular score, MS) based on the molecular features. Cox regression and Kaplan-Meier analysis were used in this study. The concordance index (C-index) was measured to compare the predicted ability between different models. The primary endpoint was overall survival (OS). RESULTS: A total of 226 patients and 23 proteins were enrolled in this study. Patients were classified into high-risk (MS-H) and low-risk (MS-L) groups based on the MS score of 227. The survival curves showed that the MS-L cohort had better 5-year and 10-year survival rates than the MS-H group (5-year OS: 51.0% vs. 8.0%; 10-year OS: 45.0% vs. 5.0%, all p < 0.001). Furthermore, multivariable analysis confirmed MS as an independent prognostic factor after eliminating the confounding factors (Hazard ratio 3.220, p < 0.001). The pT classification was confirmed to differentiate ESCC patients' prognosis (Log-rank: p = 0.029). However, the combination of pT and MS could classify survival curves evidently (overall p < 0.001), which showed that the prognostic prediction efficiency was improved significantly by the combination of the pT and MS than by the classical pT classification (C-index: 0.656 vs. 0.539, p < 0.001). CONCLUSIONS: Our study suggested an MS for significant clinical stratification of T2/3N0M0 ESCC patients to screen out subgroups with poor prognoses. Besides, the combination of pT staging and MS could predict survival more accurately for this cohort than the pT staging system alone.

7.
Am J Pathol ; 192(10): 1433-1447, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35948079

RESUMO

Costimulatory molecules are an indispensable signal for activating immune cells. However, the features of many costimulatory molecule genes (CMGs) in lung adenocarcinoma (LUAD) are poorly understood. This study systematically explored expression patterns of CMGs in the tumor immune microenvironment (TIME) status of patients with LUAD. Their expression profiles were downloaded from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Two robust TIME subtypes ("hot" and "cold") were classified by K-means clustering and estimation of stromal and immune cells in malignant tumor tissues using expression data. The "hot" subtype presented higher infiltration in activated immune cells and enrichments in the immune cell receptor signaling pathway and adaptive immune response. Three CMGs (CD80, LTB, and TNFSF8) were screened as final diagnostic markers by means of Least Absolute Shrinkage Selection Operator and Support Vector Machine-Recursive Feature Elimination algorithms. Accordingly, the diagnostic nomogram for predicting individualized TIME status showed satisfactory diagnostic accuracy in The Cancer Genome Atlas training cohort as well as GSE31210 and GSE180347 validation cohorts. Immunohistochemistry staining of 16 specimens revealed an apparently positive correlation between the expression of CMG biomarkers and pathologic response to immunotherapy. Thus, this diagnostic nomogram provided individualized predictions in TIME status of LUAD patients with good predictive accuracy, which could serve as a potential tool for identifying ideal candidates for immunotherapy.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Algoritmos , Biologia Computacional , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Aprendizado de Máquina , Prognóstico , Microambiente Tumoral/genética
8.
Ann Surg Oncol ; 30(5): 2757-2764, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36774436

RESUMO

BACKGROUND: Our study aimed to compare the short-term outcomes between robot-assisted segmentectomy (RAS) and video-assisted segmentectomy (VAS) for small pulmonary nodules. METHODS: The study included of 299 segmentectomies (132 RAS and 167 VAS procedures) for small pulmonary nodules between June 2018 and November 2021. The patients were divided into two groups: the RAS group and the VAS group. Propensity score-matching (PSM) analysis was performed to minimize bias. A logistic regression model was performed to identify the independent risk factors associated with complications. RESULTS: Before PSM, the following clinical variables were not balanced: age (P = 0.004), tumor size (P < 0.001), forced expiratory volume for 1 s (FEV1), and FEV1 percentage (P < 0.001). The patients with RAS had a shorter operative time (P = 0.014), less blood loss, a shorter postoperative hospital stay, less use of strong opioids, less drainage on postoperative day 1, and less postoperative total drainage, but more cost (all P < 0.001). Conversion to open surgery was performed for two patients in the VAS group but none in the RAS group. After PSM, 53 pairs were successfully matched. The data again suggested that the patients with RAS had less blood loss, a shorter postoperative hospital stay, and less use of strong opioids, but more cost (all P < 0.001). The operation time also was shorter in the RAS group, with a borderline statistically significant P value (0.053). CONCLUSIONS: In our study, RAS had better short-term outcomes than VAS, indicating a safer and more efficient technique than VAS.


Assuntos
Nódulos Pulmonares Múltiplos , Robótica , Humanos , Pneumonectomia/métodos , Pontuação de Propensão , Mastectomia Segmentar , Cirurgia Torácica Vídeoassistida/efeitos adversos , Estudos Retrospectivos
9.
Drug Metab Dispos ; 51(12): 1583-1590, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37775332

RESUMO

To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities. METHOD: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed. RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01). CONCLUSION: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG. SIGNIFICANCE STATEMENT: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Antineoplásicos/efeitos adversos , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Citocromo P-450 CYP2C9
10.
Opt Lett ; 48(9): 2472-2475, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37126302

RESUMO

Recently, inorganic halide perovskites, especially CsPbBr3, have been attracting attention because of their high efficiency, wide color gamut, and narrow luminescent spectrum. To elevate the perovskite devices' performance, optimizations of crystalline quality, device structures, and fabrication process are essential. Currently, the state-of-the-art fabrication approach of CsPbBr3 is spin-coating in an inert environment (nitrogen, argon, etc.), which requires temperature and humidity control. In this work, a CsPbBr3-based visible photodetector (PD) is realized in a humid atmosphere, whose performances were comparable to those reported in an inert glovebox. The dependencies of responsivity and transient time on CsBr coating layer numbers and electrode period were also investigated. The best device performance was obtained with 4 layers of CsBr coating with a responsivity of 107.2 mA/W, detectivity of 4.29 × 1010 Jones, and quantum efficiency of 25.4%. The rise time of the 3-4-layer CsBr-coated PD was reduced by the higher crystalline quality and carrier mobility, while the decay time of the 1-layer CsBr-coated PD was faster since the dense defect induced non-radiative recombination centers. With the period T increasing, the responsivity decreased, while the transient times increased. We believe that our results could benefit the future optimization of perovskite materials and PDs.

11.
Opt Lett ; 48(19): 5141-5144, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37773405

RESUMO

Indium tin oxide (ITO) is often used as a current spreading layer in the GaN-based vertical-cavity surface-emitting lasers (VCSELs). However, the absorption coefficient of ITO is significant, which reduces the laser output power, raises the threshold, and makes VCSELs hardly lase in the ultraviolet range. To find a transparent conductive structure that can replace ITO, we propose a periodic p-AlGaN/u-GaN/p-GaN structure. In the simulation of light-emitting diodes, the optimized parameter is obtained with multi-period 10 nm p-Al0.1Ga0.9N/2 nm u-GaN/8 nm p-GaN combined with n-GaN/n-Al0.2Ga0.8N in the n region. Applying the structure to 435 nm VCSELs and comparing it to a common VCSEL with the ITO current spreading layer, it can be found that the new structure reduces the threshold from 9.17 to 3.06 kA/cm2. The laser power increases from 1.33 to 15.4 mW. The optimized structure has a high laser power and a lower threshold, which can be used in future investigations.

12.
Opt Lett ; 48(15): 4117-4120, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37527132

RESUMO

Flexible optoelectronics is a technique for fabricating optoelectronic devices on a flexible substrate. Compared with conventional devices, flexible optoelectronic devices can be used in more complex working environments benefiting from the mechanical flexibility. Herein, for the first time to the best of our knowledge, a flexible GaN-based microdisk laser on a polyethylene terephthalate (PET) substrate in the ultraviolet A (UVA) range was demonstrated by using thin film transfer process based on laser lift-off (LLO). The lasing wavelength is 370.5 nm with a linewidth of 0.15 nm and a threshold power density of 200 kW/cm2. Additionally, a distributed Bragg reflector (DBR) was deposited on the backside of the microdisk as the bottom mirror between GaN microdisk and PET substrate, which can provide better mode confinement inside the microdisk and increases the oscillation intensity. The lasing wavelength of the flexible laser shows a 2-nm redshift under different bending curvature of the substrate, which is promising for applications such as mechanical sensing.

13.
Respir Res ; 24(1): 168, 2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37353782

RESUMO

BACKGROUND: The current nodal (pN) classification still has limitations in stratifying the prognosis of small cell lung cancer (SCLC) patients with pathological classifications T1-2N0-2M0. Thus. This study aimed to develop and validate a modified nodal classification based on a multicenter cohort. MATERIALS AND METHODS: We collected 1156 SCLC patients with pathological classifications T1-2N0-2M0 from the Surveillance, Epidemiology, and End Results database and a multicenter database in China. The X-tile software was conducted to determine the optimal cutoff points of the number of examined lymph nodes (ELNs) and lymph node ratio (LNR). The Kaplan-Meier method, the Log-rank test, and the Cox regression method were used in this study. We classified patients into three pathological N modification categories, new pN#1 (pN0-#ELNs > 3), new pN#2 (pN0-#ELNs ≤ 3 or pN1-2-#LNR ≤ 0.14), and new pN#3 (N1-2-#LNR > 0.14). The Akaike information criterion (AIC), Bayesian Information Criterion, and Concordance index (C-index) were used to compare the prognostic, predictive ability between the current pN classification and the new pN component. RESULTS: The new pN classification had a satisfactory effect on survival curves (Log-rank P < 0.001). After adjusting for other confounders, the new pN classification could be an independent prognostic indicator. Besides, the new pN component had a much more accurate predictive ability in the prognostic assessment for SCLC patients of pathological classifications T1-2N0-2M0 compared with the current pN classification in the SEER database (AIC: 4705.544 vs. 4731.775; C-index: 0.654 vs. 0.617, P < 0.001). Those results were validated in the MCDB from China. CONCLUSIONS: The multicenter cohort developed and validated a modified nodal classification for SCLC patients with pathological category T1-2N0-2M0 after surgery. Besides, we propose that an adequate lymph node dissection is essential; surgeons should perform and consider the situation of ELNs and LNR when they evaluate postoperative prognoses of SCLC patients.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Estadiamento de Neoplasias , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/cirurgia , Teorema de Bayes , Modelos de Riscos Proporcionais , Prognóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia
14.
BMC Cancer ; 23(1): 282, 2023 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-36978035

RESUMO

BACKGROUND: Acapella plus active cycle of breathing technique (ACBT), external diaphragm pacemaker (EDP) plus ACBT have been shown to facilitate the recovery of functional capacity and lung function in patients suffering from airway obstruction but the efficacy in perioperative patients with lung cancer has not been proven. METHODS: We conducted a three-arm, prospective, randomized, assessor-blinded, controlled trial in patients with lung cancer who underwent thoracoscopic lobectomy or segmentectomy in the department of thoracic surgery, China. Patients were randomly assigned (1:1:1) to receive Acapella plus ACBT, EDP plus ACBT, or ACBT group (control group) using SAS software. The primary outcome was functional capacity, measured by the 6-minute walk test (6MWT). RESULTS: We recruited 363 participants over 17 months: 123 assigned to the Acapella plus ACBT group, 119 to the EDP plus ACBT group, and 121 to the ACBT group. Statistically significant differences were noted for functional capacity between the EDP plus ACBT and control groups at each follow-up time (1-week follow-up: difference = 47.25 m, 95% CI, 31.56-62.93; P < 0.001; and 1-month follow-up: difference = 49.72 m, 95% CI, 34.04-65.41; P < 0.001), between the Acapella plus ACBT and control groups at postoperative week 1 (difference = 35.23 m, 95% CI, 19.30-51.16; P < 0.001) and postoperative month 1 (difference = 34.96 m, 95% CI, 19.03-50.89; P < 0.001), and between the EDP plus ACBT and Acapella plus ACBT groups at 1-month follow-up (difference = 14.76 m, 95% CI, 1.34-28.19; P = 0.0316). CONCLUSION: EDP plus ACBT and Acapella plus ACBT significantly improved functional capacity and lung function in perioperative patients with lung cancer, compared with single-model ACBT, and the effects of EDP plus ACBT were clearly superior to those of other programs. TRIAL REGISTRATION: The study was registered in the clinical trial database (clinicaltrials.gov) on June 4, 2021 (No. NCT04914624).


Assuntos
Diafragma , Neoplasias Pulmonares , Humanos , Diafragma/cirurgia , Estudos Prospectivos , Terapia Respiratória/métodos , Neoplasias Pulmonares/cirurgia , Modalidades de Fisioterapia
15.
J Org Chem ; 88(15): 11284-11298, 2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37471456

RESUMO

Hydroquinine-6'-boric acid was first synthesized via a palladium-catalyzed borylation/silica gel promoted hydrolysis sequence of hydroquinine-derived triflate and bis(pinacolato)diboron. The newly designed chiral building block was subjected to the Suzuki-Miyaura cross-coupling reaction, Petasis reaction, and selenylation reaction, respectively, and all these reactions worked well to afford the corresponding 6'-functionalized hydroquinines with satisfactory results, demonstrating its extraordinary application potency.

16.
Bioorg Med Chem Lett ; 85: 129218, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36894107

RESUMO

A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer activities against four cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC50 lowered to 0.09 µM, a far greater potency than that of mono-naphthalimide A7, mitonafide, and amonafide. A gel electrophoresis assay revealed that DNA and Topo I were the potential targets of compounds A6 and A7. The treatment of CNE-2 cells with compounds A6 and A7 resulted in an S phase cell cycle arrest, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of CDK2 and cyclin E. In addition, compounds A6 and A7-induced apoptosis was further confirmed by flow cytometry, ROS generation assay, and Hoechst 33,258 staining. In particular, in vivo antitumor assay results revealed that bisnaphthalimide A6 exhibited potent anticancer efficiency in an MGC-803 xenograft tumor model, in comparison with mitonafide, and had lower toxicity than mono-naphthalimide A7. In brief, the results suggested that bisnaphthalimide derivatives containing 3-nitro and 4-morpholine moieties might serve as DNA binding agents for the development of new antitumor agents.


Assuntos
Antineoplásicos , Humanos , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Apoptose , DNA/química , Morfolinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Estrutura-Atividade , Estrutura Molecular
17.
World J Surg Oncol ; 21(1): 78, 2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36872314

RESUMO

BACKGROUND: The purpose of our study is to investigate the expression level and prognostic value of serum α-hydroxybutyrate dehydrogenase (α-HBDH) in lung cancer (LC) patients. METHOD: LC patients treated in the Department of Oncology, Shaanxi Provincial Cancer Hospital from January 2014 to December 2016 were included in this study, all of whom underwent serological detection of α-HBDH prior to admission, and were enrolled in follow-up 5-year survival. Comparing the differences between high group and normal groups based on α-HBDH and LDH expression via clinicopathological parameters and laboratory data. Univariate and multivariate regression and overall survival (OS) were analyzed to explore whether elevated α-HBDH was an independent risk factor for LC, compared to LDH. RESULTS: Multivariate regression analysis showed that age (P = 0.018), liver metastasis (P = 0.011), α-HBDH (P = 0.015), and neutrophil-to-lymphocyte ratio (NLR) (P = 0.031) were independent prognostic factors affecting OS in LC patients. The overall diagnostic efficacy of α-HBDH (AUC = 0.887) was higher than that of LDH (AUC = 0.709) in the ROC curve. The sensitivity was significantly higher of α-HBDH (sensitivity: 76.06%, specificity: 94.87%) compared with LDH (sensitivity: 49.30%, specificity: 94.87%). The median of OS was more significant in the high-α-HBDH group (6.4 months) than in the normal-α-HBDH group (12.7 months) (P = 0.023). The median of OS was significant in the high-LDH (> 245 U/L) group at 5.8 months and 12.0 months in the normal-LDH (≤ 245 U/L) group (P = 0.068). CONCLUSIONS: Elevated expression of α-HBDH may indicate a poor prognosis of LC patients. It has a higher sensitivity than LDH and can be used as a potential early biomarker and an independent risk factor predicting the prognosis of LC survival.


Assuntos
Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Prognóstico , Institutos de Câncer , Hospitalização
18.
BMC Biol ; 20(1): 254, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357887

RESUMO

BACKGROUND: Heat stress is a major abiotic stress affecting the growth and development of plants, including crop species. Plants have evolved various adaptive strategies to help them survive heat stress, including maintaining membrane stability, encoding heat shock proteins (HSPs) and ROS-scavenging enzymes, and inducing molecular chaperone signaling. Brassinosteroids (BRs) are phytohormones that regulate various aspects of plant development, which have been implicated also in plant responses to heat stress, and resistance to heat in Arabidopsis thaliana is enhanced by adding exogenous BR. Brassinazole resistant 1 (BZR1), a transcription factor and positive regulator of BR signal, controls plant growth and development by directly regulating downstream target genes. However, the molecular mechanism at the basis of BR-mediated heat stress response is poorly understood. Here, we report the identification of a new factor critical for BR-regulated heat stress tolerance. RESULTS: We identified ERF49 in a genetic screen for proteins required for BR-regulated gene expression. We found that ERF49 is the direct target gene of BZR1 and that overexpressing ERF49 enhanced sensitivity of transgenic plants to heat stress. The transcription levels of heat shock factor HSFA2, heat stress-inducible gene DREB2A, and three heat shock protein (HSP) were significantly reduced under heat stress in ERF49-overexpressed transgenic plants. Transcriptional activity analysis in protoplast revealed that BZR1 inhibits ERF49 expression by binding to the promoter of ERF49. Our genetic analysis showed that dominant gain-of-function brassinazole resistant 1-1D mutant (bzr1-1D) exhibited lower sensitivity to heat stress compared with wild-type. Expressing ERF49-SRDX (a dominant repressor reporter of ERF49) in bzr1-1D significantly decreased the sensitivity of ERF49-SRDX/bzr1-1D transgenic plants to heat stress compared to bzr1-1D. CONCLUSIONS: Our data provide clear evidence that BR increases thermotolerance of plants by repressing the expression of ERF49 through BZR1, and this process is dependent on the expression of downstream heat stress-inducible genes. Taken together, our work reveals a novel molecular mechanism mediating plant response to high temperature stress.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Termotolerância , Brassinosteroides , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Termotolerância/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Resposta ao Choque Térmico/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Regulação da Expressão Gênica de Plantas
19.
Angew Chem Int Ed Engl ; 62(40): e202310138, 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37590086

RESUMO

The selective oxygenation of ubiquitous C(sp3 )-H bonds remains a highly sought-after method in both academia and the chemical industry for constructing functionalized organic molecules. However, it is extremely challenging to selectively oxidize a certain C(sp3 )-H bond to afford alcohols due to the presence of multiple C(sp3 )-H bonds with similar strength and steric environment in organic molecules, and the alcohol products being prone to further oxidation. Herein, we present a practical and cost-efficient electrochemical method for the highly selective monooxygenation of benzylic C(sp3 )-H bonds using continuous flow reactors. The electrochemical reactions produce trifluoroacetate esters that are resistant to further oxidation but undergo facile hydrolysis during aqueous workup to form benzylic alcohols. The method exhibits a broad scope and exceptional site selectivity and requires no catalysts or chemical oxidants. Furthermore, the electrochemical method demonstrates excellent scalability by producing 115 g of one of the alcohol products. The high site selectivity of the electrochemical method originates from its unique mechanism to cleave benzylic C(sp3 )-H bonds through sequential electron/proton transfer, rather than the commonly employed hydrogen atom transfer (HAT).

20.
Anal Chem ; 94(45): 15720-15728, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36341721

RESUMO

Post-neurosurgical meningitis (PNM) often leads to serious consequences; unfortunately, the commonly used clinical diagnostic methods of PNM are time-consuming or have low specificity. To realize the accurate and convenient diagnosis of PNM, herein, we propose a comprehensive strategy for cerebrospinal fluid (CSF) analysis based on a machine-learning-aided cross-reactive sensing array. The sensing array involves three Eu3+-doped metal-organic frameworks (MOFs), which can generate specific fluorescence responding patterns after reacting with potential targets in CSF. Then, the responding pattern is used as learning data to train the machine learning algorithms. The discrimination confidence for artificial CSF containing different components of molecules, proteins, and cells is from 81.3 to 100%. Furthermore, the machine-learning-aided sensing array was applied in the analysis of CSF samples from post-neurosurgical patients. Only 25 µL of CSF samples was needed, and the samples could be robustly classified into "normal," "mild," or "severe" groups within 40 min. It is believed that the combination of machine learning algorithms with robust data processing capability and a lanthanide luminescent sensor array will provide a reliable alternative for more comprehensive, convenient, and rapid diagnosis of PNM.


Assuntos
Meningite , Estruturas Metalorgânicas , Humanos , Procedimentos Neurocirúrgicos , Meningite/diagnóstico , Aprendizado de Máquina , Fluorescência , Líquido Cefalorraquidiano
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